Camptothecin, an alkaloid isolated from Camptotheca accuminata, is an anti-cancer agent having a broad spectrum of activity. Its insoluble nature has for a long time directed research towards the insoluble salts of the compound, the toxicity of which has proved to be a major handicap. Several other studies have been carried out with a view to obtaining structural analogues and to overcoming the lack of solubility of the natural molecule (J. Med. Chem. 1991. 34, 98; Chem. Pharm. Bull., 1991, 39, 3183). The modifications made relate principally to the A and B rings. The conclusions of different studies also show the importance of the E ring and more especially of the lactone function. In fact, the latter, in equilibrium with the open hydroxy-acid form, appears to be the most active form having reduced undesirable effects (Cancer Res., 1989, 49, 1465; ibid, 1989, 49, 5077). Attempts at modifying this ring have been carried out, in particular the cyclic oxygen atom has been replaced by a nitrogen or sulphur atom, but in each case there is a loss of pharmacological activity, so confirming the importance of the lactone (J. Med. Chem., 1989. 32, 715).
The present invention relates to camptothecin structural analogue compounds, the E ring of which has been modified. They are characterised by the replacement of the lactone function of that ring by a cyclic ketone function, the cyclic oxygen having been replaced by a carbon atom. The compounds so obtained have a novel structure and, surprisingly, have a significant cytotoxic character. It will therefore be possible to use them in the manufacture of medicaments for use in the treatment of cancerous diseases.
The invention relates to the compounds of formula (I): 
wherein:
n is 0, or 2,
R1, R2, R3, R4 and R5 are selected each independently of the others from a hydrogen atom, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a perhaloalkyl group, a (C3-C11)cycloalkyl group, a (C3-C11)cycloalkyl-alkyl group, a hydroxy group, a hydroxyalkyl group, an alkoxy group, an alkoxyalkyl group, an alkoxycarbonyl group, an acyloxy group, a carboxy group, a nitro group, a cyano group, an aminocarbonyl group (optionally substituted on the nitrogen atom by one or two alkyl groups), and the groups (CH2)pxe2x80x94NRaRb and xe2x80x94Oxe2x80x94C(O)xe2x80x94Nxe2x80x94RaRb, wherein p is an integer from 0 to 6, and Ra and Rb each independently of the other represents a hydrogen atom, an alkyl group, a (C3-C11)cycloalkyl group, a (C3-C11)cycloalkyl-alkyl group, an acyl group, an optionally substituted aryl group or an optionally substituted arylalkyl group, or Ra and Rb form together with the nitrogen atom carrying them a pyrrolyl, piperidinyl or piperazinyl group, it being possible for each of those cyclic groups to be optionally substituted, or two adjacent groups R2, R3, R4 and R5 form together with the carbon atoms carrying them a group xe2x80x94Oxe2x80x94(CH2)txe2x80x94O, t being an integer from 1 to 3 inclusive,
R60, R70n, R80 and R90 each independently of the others represents a hydrogen atom, a hydroxy group, an alkoxy group, or a group Oxe2x80x94(CO)xe2x80x94X or Oxe2x80x94(CO)xe2x80x94NXW wherein X and W each independently of the other represents an alkyl group, an alkenyl group, an alkynyl group, a (C3-C11)cycloalkyl group, a (C3-C11)cycloalkyl-alkyl group, an optionally substituted aryl group or an optionally substituted arylalkyl group,
R61, R71n, R81, and R91, each independently of the others represents a hydrogen atom, an alkyl group, an alkenyl group or an alkynyl group, or, taken in pairs on adjacent carbon atoms, together form a bond or an oxirane group, or two germinal groups (R60 and R61) and/or (R70n and R71n) and/or (R80 and R81) and/or (R90 and R91) together form an oxo group or a group xe2x80x94Oxe2x80x94(CH2)t1xe2x80x94O, t1 being an integer from 1 to 3 inclusive,
with the proviso that R60, R61, R70n, R71n, R80, R81, R90 and R91 do not all represent a hydrogen atom.
their enantiomers, diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
it being understood that
the term xe2x80x9calkylxe2x80x9d denotes a linear or branched chain having from 1 to 6 carbon atoms,
the term xe2x80x9calkenylxe2x80x9d denotes a linear or branched chain having from 2 to 6 carbon atoms and containing from 1 to 3 double bonds.
the term xe2x80x9calkynylxe2x80x9d denotes a linear or branched chain having from 2 to 6 carbon atoms and containing from 1 to 3 triple bonds,
the term xe2x80x9calkoxyxe2x80x9d denotes a linear or branched alkyl-oxy radical containing from 1 to 6 carbon atoms.
the term xe2x80x9cacylxe2x80x9d denotes a linear or branched alkyl-carbonyl radical containing from I to 6 carbon atoms.
the term xe2x80x9carylxe2x80x9d represents a phenyl or naphthyl group,
the expression xe2x80x9csubstitutedxe2x80x9d when used in relation to aryl or arylalkyl groups means that the groups in question are substituted by one or more halogen atoms, and/or groups alkyl, alkoxy, hydroxy, cyano, nitro, and/or amino (optionally substituted by one or two alkyl groups),
the expression xe2x80x9csubstitutedxe2x80x9d when used in relation to pyrrolyl, piperidinyl or piperazinyl groups means that the groups in question are substituted by one or more alkyl, alkoxy, aryl, arylalkyl, aryloxy and/or aryloxyalkyl groups.
An advantageous aspect of the invention relates to compounds of formula (I) wherein R60 represents a hydroxy group and R61 represents an alkyl group (for example ethyl).
Another advantageous aspect of the invention relates to compounds of formula (I) wherein R80 and R81, together form an oxo group, or R90 and R91 together form an oxo group, or R80 with R81 and R90 with R91 form two oxo groups. Preferred compounds of formula (I) are those wherein R1 represents a hydrogen atom.
Other preferred compounds of formula (I) are those wherein R2, R3, R4 and R5 are selected from a hydrogen atom, a halogen atom, an alkyl group and an alkoxy group, or two of those groups, when bonded to two adjacent carbon atoms, together form a methylenedioxy or ethylenedioxy group (preferably methylenedioxy). Among those compounds, preference is given to those wherein each of R2 and R5 represents a hydrogen atom.
An especially advantageous aspect of the invention relates to compounds of formula (I) wherein each of R1, R2 and R5 represents a hydrogen atom, R3 and R4 are selected from a hydrogen atom, a halogen atom, an alkyl group and an alkoxy group, or together form a methylenedioxy group, R60, R70n, R80 and R90 each independently of the others represents a hydrogen atom, a hydroxy group or an alkoxy group, and R61, R71n, R81, and R91 each independently of the others represents a hydrogen atom or an alkyl group, or, taken in pairs on adjacent carbon atoms, together form a bond or an oxirane group, or two germinal groups (R60 and R61) and/or (R70n and R71n) and/or (R80 and R81) and/or (R90 and R91) together form an oxo group.
The present invention relates also to a process for the preparation of compounds of formula (I), characterised in that there is used as starting material a compound of formula (II): 
wherein n, R60, R61, R70n, R71n, R80, R81, R90 and R91 are as defined for formula (I), which is condensed, in a basic medium, with a compound of formula (III): 
wherein R1, R2, R3, R4 and R5 are as defined for formula (I), and Hal and Halxe2x80x2 each independently of the other represents a halogen atom,
or, in accordance with the conditions of a Mitsunobu reaction, with a compound of formula (IIIxe2x80x2): 
wherein R1, R2, R3, R4, R5 and Hal are as defined hereinbefore,
to yield a compound of formula (IV): 
wherein R1, R2, R3, R4, R5, n, R60, R61, R70n, R71n, R80, R81, R90, R91 and Hal are as defined hereinbefore,
which compound (IV) is subjected to an intramolecular cyclisation reaction of the xe2x80x9cHeckxe2x80x9d type catalysed by a palladium compound, to yield a compound of formula (I), it being understood, for the purpose of simplifying the above process, that the reactive groups present in R60, R61, R70n, R71n, R80, R81, R90 and R91 can be protected by conventional protecting groups and deprotected at the appropriate time point, that the hydroxy groups present in those same positions can be oxidised by conventional chemistry methods to oxo groups, and, conversely, the oxo groups present in those same positions can be reduced by conventional reducing agents at any appropriate time point in the synthesis, and that, when two of those groups together form a bond, the latter can be introduced at any time point deemed suitable by the person skilled in the art in order to facilitate the synthesis,
which compounds of formula (I):
can be purified, if necessary, according to a conventional purification technique,
are separated, where appropriate, into their stereoisomers according to a conventional separation technique,
are converted, if desired, into addition salts thereof with a pharmaceutically acceptable acid or base.
The substrates of formulae (II) and (III) are commercial products or are prepared according to knows procedures or using conventional reactions of oyganic chemistry. By way of illustration, there may be mentioned the processes described in J. Am. Chem. Soc., 1992, 37, 10971.
In particular, it is possible to prepare a substrate of formula (IIxe2x80x2): 
wherein n, R60, R61, R70n, R71n, R80, R81, R90 and R91 are as defined for formula (I) and * indicates that the carbon atom carrying the groups R60 and R61 has a fixed configuration (R) or (S),
in order to obtain, according to the process described hereinbefore, a compound of formula (Ixe2x80x2): 
wherein R1, R2, R3, R4, R5, n, R60, R61, R70n, R71n, R80, R81, R90 and R91 are as for formula (I) and * indicates that the configuration of the carbon atom is fixed.
Among the pharmaceutical compositions according to the invention, there may be mentioned more especially those that are suitable for oral, parenteral or nasal administration, tablets or dragees, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels, etc.
The useful dosage varies according to the age and weight of the patient, the nature and severity of the disorder and the route of administration, which may be oral, nasal, rectal or parenteral. The unit dose generally ranges from 0.1 to 500 mg for a treatment in from 1 to 3 administrations per 24 hours.